Mismatch repair cancer syndrome

Overview

Mismatch repair cancer syndrome (MMRCS), also known as Constitutional Mismatch Repair Deficiency (CMMRD) syndrome, is a rare inherited cancer predisposition syndrome caused by biallelic (i.e., mutations in both copies) mutations in genes responsible for DNA mismatch repair. This syndrome significantly increases the risk of various childhood and early-onset cancers, particularly brain tumors, hematological malignancies, and gastrointestinal cancers. It is distinct from Lynch syndrome (also called hereditary nonpolyposis colorectal cancer or HNPCC), which involves monoallelic mutations in mismatch repair genes and typically affects adults.

MMRCS is inherited in an autosomal recessive manner and is often seen in families with a history of Lynch syndrome or consanguinity. Children with this syndrome are highly susceptible to developing multiple primary cancers at an early age and may also present with café-au-lait spots and other skin changes resembling neurofibromatosis type 1 (NF1), complicating the clinical picture.

Causes

Mismatch repair cancer syndrome is caused by mutations in both alleles of one of the DNA mismatch repair (MMR) genes. These genes normally help repair errors that occur during DNA replication. When both copies are defective, the body cannot effectively correct these errors, leading to a high mutation rate and increased cancer risk.

The main genes involved include:

• MLH1

• MSH2

• MSH6

• PMS2 – the most frequently mutated gene in CMMRD cases

Inheritance follows an autosomal recessive pattern, meaning both parents must carry one defective copy of the gene. The risk of a child having MMRCS is 25% if both parents are carriers.

Symptoms

Children with MMRCS may develop a range of cancers and show signs of genetic instability early in life. Common clinical features include:

Common Cancers

• Central nervous system tumors: Most notably high-grade gliomas

• Hematological malignancies: Such as T-cell lymphoblastic lymphoma and leukemia

• Colorectal cancer: Often occurs in the first or second decade of life

• Gastrointestinal polyposis: Multiple polyps in the colon or small intestine

Other Features

• Early-onset cancers (before age 18)

• Multiple primary malignancies

• Café-au-lait spots (similar to NF1)

• Other skin manifestations (e.g., axillary freckling)

• Family history of Lynch syndrome-related cancers

In some cases, physical features may resemble other genetic conditions, which can delay diagnosis without proper genetic testing.

Diagnosis

Diagnosis of MMRCS involves a combination of clinical evaluation, family history, tumor analysis, and genetic testing. Diagnostic steps include:

• Clinical assessment: History of multiple or early-onset cancers, café-au-lait spots, and consanguinity

• Immunohistochemistry (IHC): Tumor tissue is tested for loss of MMR protein expression (e.g., MLH1, MSH2, MSH6, PMS2)

• Microsatellite instability (MSI) testing: High MSI levels suggest mismatch repair deficiency

• Germline genetic testing: Confirms biallelic mutations in MMR genes

• Family genetic analysis: Identification of carrier status in parents and siblings

Because of its overlap with Lynch syndrome and other hereditary cancer syndromes, comprehensive genetic counseling and testing are essential for accurate diagnosis and family risk assessment.

Treatment

Management of mismatch repair cancer syndrome is challenging due to the early onset and aggressive nature of the cancers involved. Treatment strategies focus on both the management of existing cancers and preventive care to detect new malignancies early.

Cancer Treatment

• Surgical resection: For localized solid tumors such as colorectal or brain cancers

• Chemotherapy: Used for hematological malignancies or unresectable tumors

• Radiation therapy: May be used for CNS tumors, though with caution due to long-term risks

• Immunotherapy: Checkpoint inhibitors (e.g., PD-1 inhibitors) have shown promise due to the high mutation burden of MMR-deficient tumors

Surveillance and Prevention

• Regular colonoscopy and gastrointestinal surveillance from early childhood

• Brain MRI screening in high-risk individuals

• Blood tests and imaging to monitor for leukemia and lymphomas

• Consideration of prophylactic surgery in select high-risk cases

Genetic Counseling

• Offered to families for carrier testing and reproductive planning

• Prenatal or preimplantation genetic diagnosis may be discussed with at-risk couples

Prognosis

The prognosis for individuals with mismatch repair cancer syndrome varies depending on the type and stage of cancer at diagnosis. Due to the high likelihood of developing multiple cancers early in life, the overall prognosis is guarded, but aggressive treatment and vigilant surveillance can improve outcomes.

Key prognostic factors include:

• Type of malignancy: CNS tumors and leukemias tend to have poorer outcomes

• Early detection: Regular screening can improve survival through early intervention

• Access to advanced therapies: Immunotherapy has shown benefit in some MMR-deficient cancers

With improved genetic screening, early diagnosis, and emerging treatments like checkpoint inhibitors, the outlook for affected individuals is gradually improving. Long-term, multidisciplinary follow-up and genetic support remain essential components of care.